Ten Best Readings: Ten Best Readings in Malignant Melanoma

Merrick I. Ross, MD
Department of Surgical Oncology M.D. Anderson Cancer Center

Balch CM, Urist MM, Karakousis CP, et al. Efficacy of 2-cm surgical margins for intermediate-thickness melanomas (1 to 4 mm): results of a multi- institutional randomized surgical trial. Ann Surg. 1993;218:262-267.

Long-term follow-up of this study of 2-cm and 4-cm excision margins revealed that a 2-cm margin did not negatively impact local control or overall survival. This robust landmark study firmly established new standards of surgical care that result in less morbidity compared with previous standards. Combined with the 1-cm margin of excision standard for thin melanomas (<1 cm) previously established by the World Health Organization randomized trial, contemporary surgical guidelines are now secure for primary melanomas of varying thickness 4 mm or less.

Morton DL, Wen DR, Wong JM, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg. 1992;127:392-399.

This landmark study introduced a novel, minimally invasive surgical technique to determine if microscopic metastases are present in regional lymph nodes draining a primary cutaneous melanoma. The study demonstrated that the sentinel node, identified through an intradermal injection of a vital blue dye (Lymphazurin) around the intact primary lesion or biopsy scar, can reliably stage the regional lymph node basin. A multi-institutional trial currently is ongoing to better establish the use of this technique. Patients are randomized to receive a wide local excision of the primary melanoma alone vs wide local excision plus "selective lymphadenectomy" using lymphatic mapping and sentinel node biopsy.

Reintgen D, Cruse CW, Wells K, et al. The orderly progression of melanoma nodal metastases. Ann Surg. 1994;220:759-767.

The authors provide a compelling statistical argument that the sentinel node is a special node that can reliably determine whether occult metastases are present within the regional nodal basin. Their analysis supports the concept that specific regions of the skin drain directly to an initial node within a regional basin and that metastatic nodal involvement is not a random event. This study confirms the results of the initial lymphatic mapping trial and demonstrates continued enthusiasm within the academic surgical community for this intriguing technique.

Wang X, Heller R, Van Voorhis N, et al. Detection of submicroscopic lymph node metastases with polymerase chain reaction in patients with malignant melanoma. Ann Surg. 1994;220:768-774.

The sensitivity of the standard methods for pathologic evaluation of lymph nodes has long been questioned. The authors describe a provocative method using polymerase chain reaction (PCR) detection of tyrosinase messenger RNA (mRNA) for potentially detecting the presence of occult melanoma lymph node metastases. Although the PCR method is a potentially sensitive and efficient technique for the identification of micrometastases for patients with melanoma, long-term prospective clinical correlation studies must be completed to determine if the presence of tyrosinase mRNA in the absence of identifiable micrometastases by standard histologic technique correlates with future failure.

Lienard D, Ewalenko P, Delmotte JJ, et al. High-dose recombinant tumor necrosis factor alpha in combination with interferon gamma and melphalan in isolation perfusion of the limbs for melanoma and sarcoma. J Clin Oncol. 1992;10:52-60.

This publication summarizes the initial clinical experience in 44 patients with tumor necrosis factor (TNP) and gamma interferon in combination with melphalan used in an isolated limb perfusion circuit to treat measurable in- transit melanoma metastases of the extremities. An overall response rate of 100% was achieved with 90.5% of the responses being complete. The duration of response in unknown, but these initial findings have rekindled interest and enthusiasm for isolated limb perfusion in patients with in-transit metastases. These results have prompted the National Cancer Institute to embark on a multi-institutional prospective, randomized trial comparing isolated hyperthermic limb perfusion with melphalan alone vs melphalan, TNF, and gamma interferon.

Rosenberg SA, Lotze MT, Yang JC, et al. Prospective randomized trial of high- dose interleukin-2 alone or in conjunction with lymphokine-activated killer cells for the treatment of patients with advanced cancer. J Natl Cancer Inst. 1993;85:622-632.

Early results using either high-dose interleukin-2 alone or in combination with lymphokine-activated killer (LAK) cells or tumor-infiltrating lymphocytes led to a prospective, randomized trial of high-dose interleukin-2 alone or in combination with LAK cells. Response rates were unimpressive, although a trend toward an improved survival was shown in patients who received LAK cells in addition to high-dose interleukin-2. These results have dampened the enthusiasm for this approach in patients with advanced melanoma, especially given the associated toxicity and cost.

MacKie RM, Hole D. Audit of public education campaign to encourage earlier detection of malignant melanoma. Br Med J. 1992;304:1012-1015.

This Scottish study is the first to suggest that a massive lay and professional educational campaign can decrease the mortality from melanoma in the exposed populations. There was a downward trend for women in the west of Scotland. In contrast, education campaigns that have been in effect in Australia since the 1960s have caused decrease in tumor thickness at the time of diagnosis of melanoma but no decrease in the incidence or mortality rates.

Livingston PO, Wong GY, Adluri S, et al. Improved survival in stage III melanoma patients with GN2 antibodies: a randomized trial of adjuvant vaccination with GM2 ganglioside. J Clin Oncol. 1994;12:1036-1044.

This small randomized trial compared vaccination with GM2 ganglioside with bacillus Calmette-Guerin (BCG) vs treatment with BCG alone. GM2 induced IgM antibodies in most patients. The production of GM2 antibodies was associated with a prolonged disease-free interval and improved survival compared with the control arm of BCG alone. These data have prompted the development of a large multi-institutional phase III trial to study the effectiveness of GM2 ganglioside in a different preparation for patients who either have high-risk, thick primary lesions or have undergone resection of the regional nodal metastases. This ECOG trial will begin in late 1995.

McClay EF, Mastrangelo MJ, Sprandio JD, et al. The importance of tamoxifen to a cisplatin-containing regimen in the treatment of metastatic melanoma. Cancer. 1989;63:1292-1295.

Tamoxifen seems to be important in producing the relatively high response rate reported in this study. These results have been confirmed by other institutions. A regimen of DTIC (dacarbazine), BCNU (carmustine), cisplatin, and tamoxifen has been used as the control arm in a number of stage IV vaccine trials, attesting to its common usage for patients with stage IV metastatic melanoma.

Brichard V, Van Pel A, Wolfel T, et al. The tyrosinase gene codes for an antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas. J Exp Med. 1993;178:489-495.

The authors describe cytotoxic T lymphocyte recognition of an antigen expressed on autologous melanoma tumor cells coded by the tyrosinase gene. The tyrosinase antigen presented in the context of HLA-A2 (presently in approximately 50% of white patients) provides a potentially active target for active specific immunotherapy. This finding can provide the biologic basis for the construct of new vaccine products.

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